This invention relates generally to the chemical modification of biologically active molecules, and more particularly relates to a method for modifying biologically active molecules to increase their serum half-life.
Unfavorable pharrnacokinetics, such as a short serum half-life, can prevent the pharmaceutical development of many otherwise promising drug candidates. Serum half-life is an empirical characteristic of a molecule, and must be determined experimentally for each new potential drug. For example, with lower molecular weight polypeptide drugs, physiological clearance mechanisms such as renal filtration can make the maintenance of therapeutic levels of a drug unfeasible because of cost or frequency of the required dosing regimen. Conversely, a long serum half-life is undesirable where a drug or its metabolites have toxic side effects.
A possible solution to an undesirably short serum half-life of a pharmaceutical agent is to covalently attach to the agent molecules which may,increase the half-life. Previously, it has been shown that attachment of polymers to polypeptides may increase their serum half-lives. See, for example, European Patent Publication No. 0 442 724 A2, which describes xe2x80x9cPEGylatedxe2x80x9d interleukin-6 derivatives (i.e., interleukin derivatives bound to polyethylene glycol, or xe2x80x9cPEGxe2x80x9d) having an extended serum half-life. Attachment of drugs to polymers has also been reported to increase their water solubility, stability during storage and reduce their immunogenicity (published patent applications EP 0 539 167 A2, WO 94/13322). Conjugates of IL-2 or muteins thereof with polymers have also been reported to have reduced immunogenicity, increased solubility and increased half-lives (U.S. Pat. Nos. 5,362,852, 5,089,261, 5,281,698 and published patent application WO 90/07938).
However, the attachment of polymers can lead to decreases in drug activity. Incomplete or nonuniform attachment leads to a mixed population of compounds having differing properties. Additionally, the changes in half-lives resulting from such modifications are unpredictable. For example, conjugation of different polyethylene glycols to IL-8, G-CSF and IL- Ira produced molecules having a variety of activities and half-lives (Gaertner and Offord, (1996), Bioconjugate Chem. 7:38-44). Conjugation of IL-8 to PEG20 kD produced no change in its half-life, while conjugation of PEG20 kD to IL-Ira gave an almost seven-fold increase in half-life. Additionally, the IL-8/PEG20 kD conjugate was ten- to twenty-fold less effective than the native protein.
Accordingly, a method which is capable of increasing the serum half-life of a biologically active molecule, without seriously diminishing the biological function of the molecule, would be highly desirable.